Abstract Background: Mesenteric panniculitis is a chronic inflammatory and fibrotic disease characterized by mesenteric and pelvic infiltration with inflammatory cells, fibrosis, fat necrosis and calcification. Because of the rarity of mesenteric panniculitis, there is a lack of prospective studies on safe and appropriate treatments for this condition. Purpose and objectives: The purpose of the study is to evaluate naltrexone, an opioid antagonist with anti-inflammatory properties when administered in a low dose, as an effective therapy for symptomatic mesenteric panniculitis. Study design: Open label trial to assess the efficacy and safety of LDN in 25 patients with symptomatic mesenteric panniculitis. Study population: Patients with symptomatic mesenteric panniculitis who are at least 18 years of age with a diagnosis of mesenteric panniculitis verified within 12 months before study entry by CT scan or MRI of the abdomen and with a biopsy of the affected area which is negative for lymphoma or chronic infection, and with symptoms requiring treatment by their physician. Data analysis plan: A clinical response will be defined as diminution of symptoms as measured by the MPSAS. A biochemical response is defined as a reduction in the ESR or CRP levels. A quality of life response will be defined as an improvement in the four areas of the FANLTC score. Changes in MPSAS will be compared by Wilcoxon Rank Sum Test and Cross-table Analysis. A power calculation for the open label pilot study suggests that an 80% power is achieved if 50% of 25 patients that complete the study respond to treatment.